PROJECT SUMMARY ! Tissue-resident memory (TRM) CD8+ T cells permanently reside in non-lymphoid tissues where they are potent mediators of both host defense and inflammatory disease. We have recently demonstrated that although recruitment of activated CD8+ T cells to peripheral tissues is independent of antigen specificity, the subsequent formation of TRM cells is dependent on the presence of antigen. Since that study, we have generated preliminary data that suggests a strong correlation between IFN? expression, CD69 expression, and the induction of a TRM transcriptional profile. Included in this transcriptional profile is the transcriptional repressor Blimp-1 and the G-protein coupled receptor S1PR1. The current proposal is designed to investigate the mechanistic relationship between antigen recognition, induction of Blimp-1, and repression of S1PR1 using a combination of in vitro and in vivo approaches. Specifically, we will determine whether Blimp-1 represses S1PR1 expression directly following TCR stimulation, and whether these regulatory events are required for TRM formation following Vaccinia infection. Second, we will test whether a T cell?s affinity for antigen impacts the induction of Blimp-1 and the subsequent formation of TRM cells. These experiments will provide insight into the mechanism of TRM differentiation and could ultimately be applied to vaccination strategies or to inhibit TRM formation in the context of inflammatory skin diseases. Additionally, this fellowship application provides many opportunities to develop skills in performing and analyzing experimental results and communicating those results to a scientific audience. Development of these critical skills will encourage scientific discourse and contribute to a highly active research environment.